Although it is well-known that obesity is associated with insulin resistance and diabetes, the underlying mechanism of this link remains unclear. Recent findings in our lab indicated that JNK (c-Jun amino-terminal kinase) pathway may play a key role in this link. This proposal focuses on the molecular events leading to JNK activation and the subsequent impairment of insulin action. The hypothesis is that obesity leads to high ER stress in the liver, resulting in impairment of insulin signaling through JNK-activated serine phosphorylation of IRS 1 (insulin receptor substrate 1). To test this hypothesis: (1) ER stress will be examined in obese mouse models, and the impact of ER stress on insulin receptor signaling will be studied. (2) The role of the JNK1 pathway in ER stress-induced insulin resistance will be investigated by using JNK inhibitors and JNK1-deficient cells. (3) The roles of several key molecules involved ER stress response on insulin action will be studied by manipulating gene expression in both cultured cells and whole animals. A better understanding of the molecular mechanism of insulin resistance will eventually lead to identification of therapeutic targets for treatment and prevention of diabetes.